Synthesis of 2-aminobenzophenones

ABSTRACT

Process for synthesizing 2-aminobenzophenones such as the following formula (I): ##STR1## wherein X 1  and X 2  are substituents and r and s are 1 or 2, by reacting an anthranilic acid amide e.g. an N-alkoxy-N-alkyl anthranilic acid amide, with a halobenzene in the presence of an alkyllithium reagent.

BACKGROUND OF THE INVENTION

2-Aminobenzophenones are important intermediates in the synthesis of the benzodiazepine class of pharmaceuticals as well as other products as described by Leo H. Sternbach in Angew. Chem. Int. Ed. Engl. 1971, 10, 34 and in reviews including that by David A. Walsh in Synthesis, September 1980 pp. 677-688. Benzodiazepines such as diazepam and chlordiazepoxide are useful as anxiolytics, minor tranquilizers and antagonists of gastrin and cholecystokinin for treating disorders of the gastrointestinal, central nervous and appetite regulatory systems of mammals. References to these activities include the following U.S. Pat. Nos.:

    ______________________________________                                         2,893,992      3,243,430                                                                               3,651,046                                              3,051,701      3,261,870                                                                               3,686,308                                              3,136,815      3,267,110                                                                               3,740,442                                              3,202,661      3,297,755                                                                               4,820,834                                              3,203,990      3,341,592                                                       3,239,564      3,609,146                                                       ______________________________________                                    

The particular structural features of benzodiazepines which influence activity are described in the chapter "Ligand Interactions at the Benzodiazepine Receptor" by R. Ian Fryer in Comprehensive Medicinal Chemistry, pp. 539-566, Vol. 3, Ed. by John C. Emmett, Pergamon Press, Oxford (1990).

It is known that N-methoxy-N-methylamides combine with Grignard reagents and organolithium species in tetrahydrofuran to form ketones as described by Steven Nahm and Steven M. Weinreb in Tetrahedron Letter, Vol. 22, No. 39, pp. 3815-3813 (1981).

It is an object of the present invention to provide a facile high yield synthesis for 2-aminobenzophenones which is applicable with a wide variety of substituents.

SUMMARY OF THE INVENTION

It has been found that reaction of an anthranilic acid amide with a halobenzene in the presence of an alkyllithium results in the alkyllithium reacting preferentially with the halobenzene to form a phenyllithium which then reacts with the amide to form a ketone rather than with the amide directly.

The invention comprises a process for producing a 2-aminobenzophenone which is either unsubstituted or is substituted on the phenyl rings thereof, which comprises reacting;

i) an N-alkoxy-N-alkyl anthranilic acid amide or such where the alkoxy and alkyl groups are joined, which amide is either unsubstituted or is substituted on the phenyl ring thereof; and

ii) a halobenzene which is either unsubstituted or is substituted on the phenyl ring thereof,

in the presence of an alkyllithium compound.

Also part of the invention are novel intermediates.

DETAILED DESCRIPTION OF THE INVENTION

More particularly, the invention comprises a process for producing a 2-aminobenzophenone of the following formula (I): ##STR2## wherein X¹ is independently hydrogen, trifluoromethyl, cyano, hydroxy, loweralkyl, chlorine, fluorine, loweralkylthio, loweralkoxy, -Y-COOR¹ or -Y-NR² R³ ;

X² is independently a value of X¹ ;

Y is a direct bond or a C₁₋₄ linear or branched divalent alkyl;

R¹ is loweralkyl, cycloloweralkyl, substituted or unsubstituted phenyl or (substituted or unsubstituted phenyl)loweralkyl wherein the phenyl or phenylloweralkyl substituents may be 1 or 2 of chlorine, fluorine, loweralkyl, loweralkoxy, nitro or trifluoromethyl;

R² and R³ are independently a value of R¹ or in combination with the N of the NR² R³ group form an unsubstituted or mono or disubstituted, saturated or unsaturated, 4-7 membered heterocyclic ring or benzofused 4-7 membered heterocyclic ring, or said heterocyclic ring or said benzofused heterocyclic ring further comprises a second heteroatom selected from O and NCH₃ and the substitution is independently selected from C₁₋₄ alkyl;

r is 1 or 2; and

s is 1 or 2,

which comprises:

reacting an anthranilic acid amide of the following formula (II) with a halobenzene of the following formula (III): ##STR3## wherein Alk¹ and Alk² are independently C₁₋₄ alkyl or are joined to each other to form a 5-7 membered saturated ring with the nitrogen and oxygen atoms to which they are attached and

Hal is bromine or iodine,

in the presence of an alkyllithium compound.

As used herein, "lower alkyl" e.g. as part of loweralkoxy, means alkyl of about 1 to 6 carbons; and r and s may be 1 or 2 meaning 1 or 2X¹ or X² substituents on the phenyl rings.

The reaction conditions for the process of the invention can be adjusted according to the reactivities of the particular starting materials and reagant chosen. Thus, a reaction temperature of about -70° to -100° C. and the use of an inert solvent such as an ether, e.g. tetrahydrofuran, may be employed in most cases. The molar ratio may vary although a 1:1 ratio of N-alkoxy-N-alkyl anthranilic acid amide: halobenzene, e.g. formula (II): (III) is most appropriate.

The amount of alkyl lithium employed is at least 1 equivalent although about 2 equivalents is preferred since the alkyl lithium reagent or the intermediary phenyl lithium reagent, e.g. the reaction product of the alkyl lithium and the halobenzene (III), will react to some extent with the --NH₂ group of the anthranilic acid, e.g. of formula (II), and tie up that portion of the reagent. Thus, extra lithium reagent is usually appropriate whereby an appropriate molar ratio of formula (II): formula (III): alkyl lithium reagent is about 1:1:2. Examples of alkyl lithium reagents include methyl, ethyl, propyl, n-butyl, sec-butyl, t-butyl and n-pentyl lithium.

Formula (II) starting materials can be produced according to the following overall Reaction Scheme 1: ##STR4##

In formulae (II), (III), (IV) and (V), X¹, X², r and s are as defined for Formula (I) above while Alk¹ and Alk² are as defined for formula (II), e.g. methyl, ethyl or sec-butyl and Hal is bromine or iodine with bromine being a particular halogen.

In Reaction Scheme 1, step (a) is shown as enablement for the synthesis of starting materials for the process of the invention shown as step (c). Thus, step (a) is not necessary for the practice of the invention.

In step (a) of Reaction Scheme 1, an anthranilic acid of formula (IV) is reacted with a carbonyl source such as phosgene to yield an isatoic anhydride of formula (V). Anthranilic acids of formula (IV) are commercially available or may be synthesized according to literature references. Step (a) can be carried out as described in German Patent 500,916 and Friedl. 17, 500 (1930) as described by R. H. Clark et al. in the Journal of Organic Chemistry, Vol. 9, pp. 55-67 (1943). Alternatively, commercially available isatoic acids of formula (V) may be used or formula (V) compounds may be synthesized as otherwise described in the art.

In step (b) of Reaction Scheme 1, the isatoic anhydride (V) is reacted with an N, O-dialkylhydroxylamine of the formula HN(OAlk¹)Alk², with an important example being N,O-dimethylhydroxylamine hydrochloride. The reaction may be conducted at a temperature of about 25° to 100° C. in a solvent such as ethanol, in the presence of a base such as triethylamine if an acid addition salt of HN(OAlk¹)Alk² is used. Publications describing compounds of the formula HN(OAlk¹)Alk² include Boutin, R. H.; Rapoport, H. J.O.C. 51, 5320, (1986) and Cupps, T. L.; Boutin, R. H.; Rapoport, H. J.O.C. 50, 3972, (1985).

In step (c) of Reaction Scheme 1, the anthranilic acid amide of formula (II), e.g. an N-alkoxy-N-alkyl anthranilic acid amide is reacted with a halobenzene of formula (III) in the presence of an alkylithium to yield the 2-amino-benzophenone of formula (I) as described above. The halobenzene (III) may be obtained commercially or may be synthesized according to literature references such as H. G. Fletcher in Methods Carbohydr. Chem. 1963, II 166; by R. F. Cunico et al in J. Org. Chem. 1980, 45, 4797; and by L. J. Mathias in Synthesis 1979, 561. Recovery and purification of the product (I) may be by techniques known in the art including crystallization and column chromatography.

Preferably, the halobenzene of formula (III) does not have an electrophilic substituent ortho to the incipient anion, i.e. the location of Hal on the ring, or an acidic hydrogen or an ortho chloro or ortho- or para-nitro substitutent since yields tended to diminish in such cases. In addition, if X¹ or X² is to be hydroxy, it will usually be protected before step (c) and deprotected after the reaction, e.g. with a benzyl or t-butyl diphenyl silyl group.

Also part of the present invention are novel intermediates including those of formula (II).

In the following examples and throughout the specification, the following abbreviations may be used: g (grams); ml (milliliters); mmol (millimoles); min (minutes); N (normal); b.p. (boiling point); m.p. (melting point); Ph (phenyl); Bu (butyl); and EtOAc (ethyl acetate). Unless otherwise indicated, all temperatures are reported in °C. (degrees Centigrade) and pressure in mm of Hg (millimeters of mercury).

EXAMPLE 1

(a) To a solution of N,O-dimethylhydroxylamine hydrochloride (51.2 g, 0.53 mmol) in 90-95% aqueous ethanol (200 ml) is added triethylamine (53 g, 0.53 mmol) and, after 10 minutes stirring at 25° C., isatoic anhydride (37.0 g, 0.35 mmol) in portions. The reaction is then heated at reflux for 1.5 hrs and poured onto an equal volume of ice and saturated sodium bicarbonate. The ethanol is then removed by rotary evaporation, the resulting aqueous mixture extracted with ethyl acetate (3×150 ml), the combined extracts washed with water, brine, dried over magnesium sulfate and activated charcoal, and concentrated to an orange oil. The oil is chromatographed on silica gel (1:1 diethyl ether:hexanes, then acetone) and distilled to give N-methoxy-N-methyl anthranilic acid amide as a pale yellow oil; yield 47.4 g (75%); b.p. 148°-151° C./0.35 mm.

    ______________________________________                                         Elemental Analysis for C.sub.9 H.sub.12 N.sub.2 O.sub.2                                 % C        % H    % N                                                 ______________________________________                                         Found:     59.72        6.78   15.47                                           Calculated:                                                                               59.99        6.71   15.55                                           ______________________________________                                    

(b) To a mixture of N-methoxy-N-methyl anthranilic acid amide prepared as in Example 1(A)(2.00 g, 11.1 mmol) and 4-benzyloxy-bromobenzene (2.92 g, 11.1 mmol) in anhydrous tetrahydrofuran (65 ml) at -78° C. under nitrogen is added, with vigorous stirring, n-BuLi in hexanes (13.8 ml, 1.6M, 22.2 mmol) at 0.60 ml/min. After 20 min, aqueous hydrochloric acid is added (1N, 20 ml), the mixture extracted with ethyl acetate (150 ml), ethyl acetate washed with water, brine, dried over magnesium sulfate, and concentrated. Recrystallization from hexanes gave 4'-benzyloxy-2-aminobenzophenone as yellow crystals; yield: 2.35 g, (70%); m.p. 99°-101° C.

    ______________________________________                                         Elemental Analysis for C.sub.20 H.sub.17 NO.sub.2 :                                     % C        % H    % N                                                 ______________________________________                                         Found:     79.12        5.66   4.54                                            Calculated:                                                                               79.18        5.65   4.62                                            ______________________________________                                    

EXAMPLES 2-17

Following the procedure of Example 1(b) and substituting an equimolar amount of the appropriate aryl bromide for 4-benzyloxy-bromobenzene, the desired 2-aminobenzophenones were obtained as indicated in the following Table 1. In Table 1, compounds recovered as oils were purified by column chromatography using silica gel and a mixture EtOAc and hexanes as the eluant.

                                      TABLE I                                      __________________________________________________________________________     Products of Formula (I) where X.sup.1 = H, r = 1 and s = 1                                            Elemental Analysis                                                             Calculated                                                                               Found                                         X.sup.2   Temp.                                                                              Yield                                                                              M.P. C  H  N   C  H  N                                       __________________________________________________________________________     p-OCH.sub.2 Ph                                                                           -78  70%                                                                                99-101                                                                             79.19                                                                             5.65                                                                              4.62                                                                               79.12                                                                             5.66                                                                              4.54                                    H         -78 70  103-104                                                                             79.16                                                                             5.62                                                                              7.10                                                                               79.09                                                                             5.63                                                                              7.06                                    o-CH.sub.3                                                                               -78 55  79-81                                                                               79.60                                                                             6.20                                                                              6.63                                                                               79.53                                                                             6.24                                                                              6.62                                    m-CH.sub.3                                                                               -78 70  68-69                                                                               79.60                                                                             6.20                                                                              6.63                                                                               79.47                                                                             6.25                                                                              6.61                                    p-CH.sub.3                                                                               -78 68  91-92                                                                               79.60                                                                             6.20                                                                              6.63                                                                               79.43                                                                             6.25                                                                              6.59                                    o-OCH.sub.2 Ph                                                                           -78 68  108-109                                                                             79.19                                                                             5.65                                                                              4.62                                                                               79.09                                                                             5.64                                                                              4.62                                    m-OCH.sub.2 Ph                                                                           -78 67  106-107                                                                             79.19                                                                             5.65                                                                              4.62                                                                               78.89                                                                             5.70                                                                              4.61                                    o-CH.sub.2 OSiPh.sub.2 t-Bu                                                              -78 47  oil  77.38                                                                             6.71                                                                              3.01                                                                               77.20                                                                             6.74                                                                              2.95                                    m-CH.sub.2 OSiPh.sub.2 t-Bu                                                              -78 50  oil  77.38                                                                             6.71                                                                              3.01                                                                               77.44                                                                             6.73                                                                              3.00                                    p-CH.sub.2 OSiPh.sub.2 t-Bu                                                              -78 50  106-108                                                                             77.38                                                                             6.71                                                                              3.01                                                                               77.28                                                                             6.74                                                                              3.00                                    m-Cl      -100                                                                               51  79-80                                                                               67.40                                                                             4.35                                                                              6.05                                                                               67.31                                                                             4.38                                                                              6.00                                    p-Cl      -100                                                                               55  100-102                                                                             67.40                                                                             4.35                                                                              6.05                                                                               67.33                                                                             4.39                                                                              6.01                                    o-F       -100                                                                               35  124-125                                                                             72.55                                                                             4.68                                                                              6.51                                                                               72.45                                                                             4.71                                                                              6.48                                    m-CN      -100                                                                               34  114-115                                                                             75.66                                                                             4.54                                                                              12.60                                                                              75.57                                                                             4.56                                                                              12.53                                   p-CN      -100                                                                               40  157-159                                                                             75.66                                                                             4.54                                                                              12.60                                                                              75.39                                                                             4.59                                                                              12.51                                   m-CO.sub.2 t-Bu                                                                          -100                                                                               52  129-130                                                                             72.71                                                                             6.44                                                                              4.71                                                                               72.60                                                                             6.47                                                                              4.69                                    p-CO.sub.2 t-Bu                                                                          -100                                                                               51  oil  72.71                                                                             6.44                                                                              4.71                                                                               72.74                                                                             6.47                                                                              4.68                                    __________________________________________________________________________

EXAMPLES 18-22

Typical Compounds of formula (I) which may be prepared in accordance with the present invention include those of Table II:

                  TABLE II                                                         ______________________________________                                         X.sup.1  R     position   X.sup.2                                                                               s   position                                  ______________________________________                                         Cl       1     4          H      1   --                                        H        1     --         CH.sub.3                                                                              2   o,p                                       CF.sub.3 1     6          Cl     1   m                                         OCH.sub.3                                                                               2     4,5        H      1   --                                        H        1     --         CF.sub.3,Cl                                                                           2   o,p                                       ______________________________________                                     

What is claimed is:
 1. A process for producing a 2-aminobenzophenone which is either unsubstituted or is substituted on the phenyl rings thereof, which comprises reacting:i) an N-alkoxy-N-alkyl anthranilic acid amide or such amide where the alkoxy and alkyl groups are joined which amide is either unsubstituted or is substituted on the phenyl ring thereof; and ii) an iodobenzene or bromobenzene compound which is either unsubstituted or is substituted on the phenyl ring thereof,in the presence of at least 1 equivalent of an alkyllithium compound relative to the iodobenzene or bromobenzene compound.
 2. The process of claim 1, wherein the temperature of the reaction is about -70° to -100° C.
 3. The process of claim 1, with the reaction is conducted in an ether solvent.
 4. The process of claim 3, wherein said solvent is tetrahydrofuran.
 5. The process of claim 1, wherein the reaction is conducted in a single reaction vessel by adding the alkyllithium to a mixture of the anthranilic acid amide and iodobenzene or bromobenzene.
 6. A process for producing a 2-aminobenzophenone of the following formula (I): ##STR5## wherein X¹ is independently hydrogen, trifluoromethyl, cyano, hydroxy, loweralkyl, chlorine, fluorine, loweralkythio, loweralkoxy, -Y-COOR¹ or -Y-NR² R³ ;X² is independently a value of X¹ ; Y is a direct bond or a C₁₋₄ linear or branched divalent alkyl; R¹ is loweralkyl, cycloloweralkyl, substituted or unsubstituted phenyl or (substituted or unsubstituted phenyl)loweralkyl wherein the phenyl or phenylloweralkyl substituents may be 1 or 2 of chlorine, fluorine, loweralkoxy, nitro or trifluoromethyl; R² and R³ are independently a value of R¹ or in combination with the N of the NR² R³ group form an unsubstituted or mono or disubstituted, saturated or unsaturated, 4-7 membered heterocyclic ring or benzofused 4-7 membered heterocyclic ring, or said heterocyclic ring or said benzofused heterocyclic ring further comprises a second heteroatom selected from O and NCH₃ and the substitution is independently selected from C₁₋₄ alkyl; r is 1 or 2; and s is 1 or 2,which comprises: reacting an anthranilic acid amide of the following formula (II) with a halobenzene of the following formula (III): ##STR6## wherein Alk¹ and Alk² are independently C₁₋₄ alkyl or are joined to each other to form a 5-7 membered saturated ring with the nitrogen and oxygen atoms to which they are attached; and Hal is bromine or iodine,in the presence of at least 1 equivalent of an alkyllithium compound relative to halobenzene (III).
 7. The process of claim 6, wherein the temperature of the reaction is about -70° to -100° C.
 8. The process of claim 6, with the reaction is conducted in an ether solvent.
 9. The process of claim 8, wherein said solvent is tetrahydrofuran.
 10. The process of claim 6, wherein the reaction is conducted at a molar ratio of (II):(III):alkyllithium of about 1:1:2.
 11. The process of claim 6, wherein the reaction is conducted in a single reaction vessel by adding the alkyllithium to a mixture of the anthranilic acid amide (II) and halobenzene (III).
 12. The process of claim 6, wherein X¹ and X² are hydrogen, chlorine or fluorine and r and s are
 1. 13. The process of claim 12, wherein one of X¹ and X² is chlorine and the other is hydrogen.
 14. The process of claim 6, wherein Alk¹ and Alk² are methyl.
 15. The process of claim 6, wherein Hal is bromine. 